Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but also plays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whose concentration in the plasma increases 1000-fold or more during a systemic inflammatory response before returning to near undetectable levels. However, SAA is also persistently elevated in chronic inflammatory conditions such as diabetes, obesity, rheumatoid arthritis, etc. While the liver is the major source of SAA during an acute inflammatory response, extra-hepatic expression has also been documented. Most notably, adipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognized for decades that plasma levels of SAA predict cardiovascular risk in humans. More recently, our group determined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerous reports by multiple laboratories, SAA exerts a myriad of effects in vitro that would be expected to exacerbate inflammation and atherosclerosis in vivo. However, most of these published studies investigated lipid-free SAA, overlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances, plasma SAA is found associated with the high-density lipoprotein (HDL) fraction, and accumulating evidence demonstrates that HDL inhibits SAA?s pro-inflammatory activity. Thus, one function of HDL may be to sequester and neutralize SAA and limit the propagation of inflammation in vivo. Notably, SAA can also be detected on apoB particles, particularly in human populations with increased risk for cardiovascular disease. Although the pathophysiological significance of the association of SAA with non-HDL lipoproteins is not known, we have shown that SAA on apoB-containing lipoproteins augments their proteoglycan binding, which could lead to increased vascular retention. Taken together, these observations lead us to propose that the pro- inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium between HDL-SAA, very low-density lipoprotein/low-density lipoprotein-SAA, and lipid-free SAA. To test this hypothesis, we have developed critical research tools, including novel mouse models with inducible, tissue-specific SAA expression, to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodeling factors (e.g., cholesterol ester transfer protein, phospholipase A2 and oxidation) leads to the release of bioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoB lipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA (liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. The results of this proposal will validate SAA as a therapeutic target in cardiovascular disease, and will develop SAA lipoprotein distribution as a potential biomarker of risk.